Single-Cell Transcriptional Profiling of Aortic Endothelium Identifies a Hierarchy from Endovascular Progenitors to Differentiated Cells

Lukowski, Samuel W.; Patel, Jatin; Andersen, Stacey; Sim, Susan Elliott; Wong, Ho Yi; Tay, J. S. H.; Winkler, Ingrid G.; Powell, Joseph E.; Khosrotehrani, Kiarash

doi:10.1016/j.celrep.2019.04.102

Cited by 89 publications

(97 citation statements)

References 42 publications

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“…Two distinct developmental origins give rise to endothelial cells in mature blood vessels [94]. Heritable factors from these different origins may explain why proliferative endothelial cells exist alongside cells with a lower proliferative potential [72,73], and give rise to clusters of endothelial cells with similar properties via clonal expansion [37,38]. Interactions between heritable factors and local environmental conditions may also explain endothelium dysfunction in obesity.…”

Section: Discussionmentioning

confidence: 99%

Disrupted endothelial cell heterogeneity and network organization impair vascular function in prediabetic obesity

et al. 2020

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Background: Obesity is a major risk factor for diabetes and cardiovascular diseases such as hypertension, heart failure, and stroke. Impaired endothelial function occurs in the earliest stages of obesity and underlies vascular alterations that give rise to cardiovascular disease. However, the mechanisms that link weight gain to endothelial dysfunction are ill-defined. Increasing evidence suggests that endothelial cells are not a population of uniform cells but are highly heterogeneous and are organized as a communicating multicellular network that controls vascular function. Purpose: To investigate the hypothesis that disrupted endothelial heterogeneity and network-level organization contribute to impaired vascular reactivity in obesity. Methods and results: To study obesity-related vascular function without complications associated with diabetes, a state of prediabetic obesity was induced in rats. Small artery diameter recordings confirmed nitric-oxide mediated vasodilator responses were dependent on increases in endothelial calcium levels and were impaired in obese animals. Single-photon imaging revealed a linear relationship between blood vessel relaxation and population-wide calcium responses. Obesity did not alter the slope of this relationship, but impaired calcium responses in the endothelial cell network. The network comprised structural and functional components. The structural architecture, a hexagonal lattice network of connected cells, was unchanged in obesity. The functional network contained sub-populations of clustered specialized agonist-sensing cells from which signals were communicated through the network. In obesity there were fewer but larger clusters of sensory cells and communication path lengths between clusters increased. Communication between neighboring cells was unaltered in obesity. Altered network organization resulted in impaired, population-level calcium signaling and deficient endothelial control of vascular tone. Conclusions: The distribution of cells in the endothelial network is critical in determining overall vascular response. Altered cell heterogeneity and arrangement in obesity decreases endothelial function and provides a novel framework for understanding compromised endothelial function in cardiovascular disease.

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Section: Discussionmentioning

confidence: 99%

Disrupted endothelial cell heterogeneity and network organization impair vascular function in prediabetic obesity

et al. 2020

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“…Additionally, mitochondrial metabolism is a key regulatory mechanism in stem cell fate decision [40]. Samual and coworkers reported that mitochondrial metabolism is higher in endovascular progenitor cells than that in differentiated endothelial cells [41]. On the other hand, higher mitochondrial reads in scRNA-seq might be due to presence of cells of low quality resulting from damages during cell dispersion.…”

Section: Discussionmentioning

confidence: 99%

Revealing Cellular Heterogeneity and In Vitro Differentiation Trajectory of Cultured Human Endometrial Mesenchymal-like Stem Cells Using Single-cell RNA Sequencing

Cao¹,

Chan

et al. 2020

Preprint

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Endometrial mesenchymal-like stem cells (eMSCs) are adult stem cells contributing to endometrial regeneration. One set of perivascular markers (CD140b + CD146 + ) have been widely used to enrich eMSCs. Although eMSCs are easily accessible for regenerative medicine and have long been studied, their cellular heterogeneity and molecular program controlling their expansion and differentiation in vitro remains largely unclear. In this study, we applied 10X genomics single-cell RNA sequencing to eMSCs cultured in vitro after microbeading from 7 donors to investigate cellular heterogeneity in an unbiased manner. Corresponding clonogenic progenies of eMSCs after culture for 14 days were also sequenced to construct the in vitro differentiation trajectory of eMSCs. Transcriptomic expression based clustering revealed several subpopulations in eMSCs. Each subpopulation manifested distinct functional characteristics associated with immunomodulation, proliferation, extracellular matrix organization and cell differentiation. Pseudotime trajectory analysis on eMSCs and their differentiated progenies identified in vitro differentiation hierarchy of eMSCs. Further ligand-receptor pair analysis found that WNT signaling, NOTCH signaling, TGF-beta signaling and FGF signaling were important regulatory pathways for eMSC self-renewal and differentiation. By comparing eMSCs to Wharton's Jelly MSCs and adipose-derived MSCs, we found these 3 kinds of MSCs expressed largely overlapping differentiation (CD) genes and highly variable genes. In summary, we reveal for the first time high molecular and cellular heterogeneity in cultured eMSCs, and identify the key signaling pathways that may be important for eMSC differentiation.

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“…The functional significance of endothelial cell heterogeneity is only beginning to emerge. As an example, a distinct subpopulation of aortic endothelial cells with self-renewal capacity drives tissue repair 63 . In some tissues, heterogeneous cell populations may organize into spatial domains with coherent gene expression 64 , and it is thought that such multicellular groups form microcircuits, the building blocks of information processing.…”

Section: Discussionmentioning

confidence: 99%

“…Heritable factors from these different origins may explain why proliferative endothelial cells exist alongside cells with a lower proliferative potential 63,71 , and give rise to clusters of endothelial cells with similar properties via clonal expansion 37,38 . Interactions between heritable factors and local environmental conditions may also explain endothelium dysfunction in obesity.…”

Section: Discussionmentioning

confidence: 99%

Disrupted Endothelial Cell Heterogeneity and Network Organization Impairs Vascular Function in Prediabetic Obesity

Wilson

Zhang

Lee

et al. 2020

Preprint

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Rationale: Obesity is a major risk factor for diabetes and cardiovascular diseases such as hypertension, heart failure, and stroke. Impaired endothelial function occurs in the earliest stages of obesity and underlies vascular alterations giving rise to cardiovascular disease. However, the mechanisms that link weight gain to endothelial dysfunction are ill-defined. Increasing evidence suggests that, rather than being a population of uniformly responding cells, neighboring endothelial cells are highly heterogeneous and are organized as a communicating multicellular network that controls vascular function.Objective: To investigate the hypothesis that disrupted endothelial heterogeneity and network-level organization contributes to impaired vascular reactivity in obesity. Methods and Results:To study obesity-related vascular function without the complications associated with diabetes, we induced a state of prediabetic obesity in rats. Small artery diameter recordings confirmed nitric-oxide mediated vasodilator responses were dependent on increases in endothelial calcium levels and were impaired in obese animals. Single-photon imaging revealed a linear relationship between blood vessel relaxation and network-level calcium responses. Obesity did not alter the slope of this relationship, but impaired network-level endothelial calcium responses. The network itself was comprised of structural and functional components. The structural component, a hexagonal lattice network of endothelial cells, was unchanged in obesity. The functional network contained subpopulations of clustered agonist-sensing cells from which signals were communicate through the network. In obesity there were fewer but larger clusters of agonist-sensing cells and communication path lengths between clusters was increased. Communication between neighboring cells was unaltered in obesity. Altered network organization resulted in impaired, population-level calcium signaling and deficient endothelial control of vascular tone. Specialized subpopulations of endothelial cells had increased agonist sensitivity. These agonistresponsive cells were spatially clustered in a non-random manner and drove network level calcium responses. Communication between adjacent cells was unaltered in obesity, but there was a decrease in the size of the agonist-sensitive cell population and an increase in the clustering of agonist-responsive cells Conclusions: The distribution of cells in the endothelial network is critical in determining overall vascular function. Altered cell heterogeneity and arrangement in obesity decrease endothelial function and provide a novel framework for understanding compromised endothelial function in cardiovascular disease.

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Single-Cell Transcriptional Profiling of Aortic Endothelium Identifies a Hierarchy from Endovascular Progenitors to Differentiated Cells

Abstract: Highlights d scRNA sequencing reveals two distinct aortic endothelial populations d Sequencing analysis confirms transitionary cells rather than discrete populations d Endovascular progenitors are slow cycling and have distinct mitochondrial content

Cited by 89 publications

References 42 publications

Disrupted endothelial cell heterogeneity and network organization impair vascular function in prediabetic obesity

Disrupted endothelial cell heterogeneity and network organization impair vascular function in prediabetic obesity

Revealing Cellular Heterogeneity and In Vitro Differentiation Trajectory of Cultured Human Endometrial Mesenchymal-like Stem Cells Using Single-cell RNA Sequencing

Disrupted Endothelial Cell Heterogeneity and Network Organization Impairs Vascular Function in Prediabetic Obesity

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